Polymers containing pendant acid functionalities and labile backbone bonds

ABSTRACT

The instant invention is directed to a polymer with at least one labile backbone bond per repeat unit and at least one pendant acid functionality per thousand repeat units. 
     The instant invention is also directed to a controlled release device which comprises: 
     (A) a polymer with at least one labile backbone bond per repeat unit and at least one pendant acid functionality per thousand repeat units; and 
     (B) a beneficial substance incorporated within or surrounded by the matrix of said polymer.

This is a division of application Ser. No. 618,002 filed June 6, 1984now U.S. Pat. No. 4,639,366.

BACKGROUND OF THE INVENTION

There has long been a need in the field of drug delivery devices to havea drug released in the human or animal tissue at the place where it ismost therapeutically effective and to have said drug released in thetissue in a controlled manner over a long period of time.

U.S. Pat. Nos. 4,093,709 and 4,304,767 disclose polymers which can beused as a matrix to contain a drug. The polymers contain labile backbonebonds which hydrolyze in the presence of water causing a controllederosion of the matrix and resultant release of the drug. These polymershave the disadvantage, however, that they hydrolyze extremely slowly.

The polymers of the instant invention have the advantage that thependant acid functionalities catalyze the hydrolysis of the labilepolymer backbone bonds.

DESCRIPTION OF THE INVENTION

The instant invention is directed to a polymer with at least one labilebackbone bond per repeat unit and at least one pendant acidfunctionality per thousand repeat units.

The instant invention is also directed to a controlled release devicewhich comprises:

(A) a polymer with at least one labile backbone bond per repeat unit andat least one pendant acid functionality per thousand repeat units; and

(B) a beneficial substance incorporated within or surrounded by thematrix of said polymer.

The polymers of the instant invention may be prepared by reacting apolyol, preferably a diol, having a pendant acidic group with a polymercontaining a labile backbone bond. Excess amounts of either componentmay be used in preparing the final polymer, although stoichiometricamounts are preferred.

U.S. Pat. Nos. 4,093,709 and 4,304,767, which are hereby incorporated byreference, disclose numerous polyols. Any of these polyols may bemodified to contain one or more pendant acidic groups per thousandrepeat units, up to a maximum of one per repeat unit. The number of acidgroups incorporated depends on the desired rate of erosion. Forincreased erosion, relatively more acid groups would be incorporated. Apreferred group of polyols may be represented as follows: ##STR1## whereX is the acidic group and Y is a spacer group. R and Y may be an alkyl,aryl or substiuted alkyl or aryl, preferably containing 1 to 18 carbonatoms, most preferably 2 to 10 carbon atoms. The Y group may optionallybe eliminated.

Any acidic group may be used in the polyol. Examples include carboxylic,carbon acid, phosphoric, sulfonic and sulfenic acid groups.

Tri- and higher hydroxyl functional polyols may be used, which willresult in crosslinked polymers.

Any polymer containing at least one acid labile backbone bond per repeatunit (preferably two per repeat acid unit) may be used to react with thepolyol containing a pendant acid group. Examples include polyorthoesters(including polyorthocarbonates), polyacetals, polyketals, polyesters andpolyphosphazenes. The preferred polymers are poly(orthoesters) andpolyacetals. Examples of polyorthoesters, polyorthocarbonates andpolyacetals are disclosed in U.S. Pat. Nos. 4,093,709, and 4,304,767,4,221,779 and 4,150,108 which are hereby incorporated by reference.

The preparation of the polymers may be by a variety of methods. U.S.Pat. No. 4,093,709, column 8, line 11 through column 9, line 47,outlines several methods of preparation.

Any beneficial substance (e.g. therapeutics or biologically activeagents) may be used in the controlled release device. The substanceshould not significantly interfere with the acid catalyzed hydrolysis ofthe labile polymer backbone bond. Basic substances may cause someinterference. It is preferred that any acid substances be in the saltform.

Representative examples of the polyols are as follows:9,10-dihydroxystearic acid; 3,6-dihydroxynaphthalene-2,7-disulfonicacid; 2,4-dihydroxybenzoic acid; 3,4-dihydroxycinnamic acid;6,7-dihydroxy-2-naphthalene sulfonic acid; 6,7-dihydroxy-2-naphtalenesulfenic acid; 2,5-dihydroxyphenylacetic acid;2,4-dihydroxypyrimidine-5-carboxylic acid;4,8-dihydroxyquinoline-2-carboxylic acid; and mixtures thereof.

It will be realized that these are merely representative examples andthat any polyol containing an acidic group can be used provided it doesnot adversely affect the polymerization reaction or leads totoxicologically undesirable degradation products. Thus, any group thatcan be incorporated into the polymer and which when placed in waterionizes to produce a pH lower than about 7.0 is a useful group providedthe above limitations are met.

The molecular weight of the polymer is not critical. The molecularweight is preferably at least 1,000 as determined by low angle lightscattering.

Representative beneficial substances (therapeutics and biologicallyactive agents) for incorporation into or to be surrounded by the polymermatrix to be used with this invention and to be released to an aqueousenvironment include without limitation, the following:

1. Protein drugs such as insulin;

2. Desensitizing agents such as ragweed pollen antigens, hay feverpollen antigens, dust antigen and milk antigen;

3. Vaccines such as smallpox, yellow fever, distemper, hog cholera, fowlpox, antivenom, scarlet fever, dyptheria toxoid, tetanus toxoid, pigeonpox, whooping cough, influenzae, rabies, mumps, measles, poliomyelitis,Newcastle disease, etc.;

4. Anti-infectives, such as antibiotics, including penicillin,tetracycline, chlortetracycline bacitracin, nystatin, streptomycin,neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, anderythromycin; sulfonamides, including sulfacetamide, sulfamethizole,sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole,cefoxitin; anti-virals including idoxuridine; and other anti-infectivesincluding nitrofurazone and sodium propionate;

5. Antiallergenics such as antazoline, methapyrilene, chlorpheniramine,pyrilamine and prophenpyridamine;

6. Steroidal anti-inflammatory agents such as hydrocortisone, cortisone,hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone21-phosphate, and prednisolone acetate;

7. Decongestants such as phenylephrine, naphazoline, andtetrahydrazoline;

8. Miotics such as pilocarpine, eserine salicylate, carbachol,diisopropyl fluorophosphate, phospholine iodide, and demecarium bromide;

9. Anticholinergics such as atropine sulfate, cyclopentolate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine;

10. Sympathomimetics such as epinephrine;

11. Sedatives and Hypnotics such as pentabarbital sodium, phenobarbital,secobarbital sodium, codeine, (α-bromoisovaleryl)urea, carbromal;

12. Psychic Energizers such as 3-(2-aminopropyl)indole acetate,3-(2-aminobutyl)indole acetate and amitriptyline;

13. Tranquilizers such as reserpine, chlorpromazine, thiopropazate andperphenazine;

14. Androgenic steroids such as methyltestosterone and fluorymesterone;

15. Estrogens such as estrone, 17 β-estradiol, ethinyl estradiol, anddiethyl stilbesterol;

16. Progestational agents such as progesterone, megestrol, melengestrol,chlormadinone, ethisterone, norethynodrel, 19-nor-progesterone,norethindrone, medroxyprogesterone and 17 β-hydroxy-progesterone;

17. Humoral agents such as the prostaglandins, for example PGE₁, PGE₂and PGF₂ ;

18. Antipyretics analgesics such as aspirin, sodium salicylate,salicylamide, and diflunisal;

19. Antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine bromide;

20. Antimalarials such as the 4-aminoquinolines, 8-aminoquinolines,chloroquine, and pyrimethamine;

21. Antihistamines such as diphenhydramine, dimenhydrinate,tripelennamine, perphenazine, and chlorophenazine;

22. Cardioactive agents such as dibenzhydroflumethiazide, flumethiazide,hydrochlorothiazide chlorothiazide, and aminotrate;

23. Non-steroidal anti-inflammatory agents such as indomethacin andsulindac;

24. Antiparkinsonian agents such as L-dopa;

25. Antihypertensive agents such as methyldopa;

26. β-Adrenergic blocking agents such as propanolol and timolol;

27. Nutritional agents such as vitamins, essential amino acids andessential fats.

Other drugs having the same or different physiological activity as thoserecited above can be employed in drug-delivery systems within the scopeof the present invention.

Other benificent compounds which can be released in a controlled mannerover time can also be incorporated in the present invention. Theseinclude but are not limited to herbicides, pesticides, fertilizers,antifouling agents, biocides (germacides). One skilled in the art wouldrealize that any beneficial substances which are released to the aqueousatmosphere can be used in this invention.

Drugs or therapeutically beneficial substances can be in various forms,such as uncharged molecules, components of molecular complexes, ornonirritating, pharmacologically acceptable salts such as hydrochloride,hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate,tartrate, salicylate, etc. For acidic drugs, salts of metals, amines, ororganic cations (e.g., quaternary ammonium) can be employed.Furthermore, simple derivatives of the drugs (such as ethers, esters,amides, etc.) which have desirable retention and release characteristicsbut which are easily hydrolyzed by body pH, enzymes, etc., can beemployed.

The amount of drug or beneficial substance incorporated into the polymermatrix will vary greatly depending on the particular drug, the desiredtherapeutic effect and the time span in which the polymer matrix iseroded to release the particular drug. Thus, there is no critical upperlimit on the amount of drug incorporated in the polymer matrix and thelower limit will also depend on the activity of the drug (usually atleast 0.1%, preferably 0.1 to 30%, by weight, based on the total weightof the device) and the time span for the erosion of the polymer andsubsequently the drug release. Thus, it is not practical to define arange for the therapeutically effective amount of drug to beincorporated in the novel polymer matrixes of the instant invention.

Also in the case of the drug or other beneficial substance incorporatedinto the polymer matrix as stated above, the amount of drug orbeneficial substance will depend on the type of drug or substance forthe condition being treated and can generally be up to 70% of thepolymer matrix by weight.

The drug or other beneficial substance can be administered in variousways and shapes. For example, the polymer/drug or beneficial substancecan be incorporated into disc-shaped devices, rods or sheets for underthe skin implantation, spherical shapes and the like. Those skilled inthe art would realize that the invention can be incorporated in anyshaped device for the particular application it is being used for.

The above described devices can be prepared by, for example:

1. Methods of preparation include:

(1) Dissolution of components in solvent, evaporation of solvent,compression of matrix; (2) Mechanical milling of polymer and drug orother beneficial substance followed by compression; (3) Melt mixing ofpolymer and drug or other beneficial substance. In all cases, aftermixing, standard pharmaceutical technology is used to make the dosageform.

At least enough water must be present in contact with the polymer tocause degradation. Water in excess of this amount will not materiallyeffect the performance of the invention.

When the polymer is exposed to water, the acid functionality of thepolymer slowly catalyzes the hydrolysis of the labile backbone bond ofthe polymer, and the beneficial substance is released at a controlledrate.

EXAMPLE 1

16.30 g (0.113 moles) of trans-cyclohexanedimethanol, 8.15 g (0.069moles) of 1,6-hexanediol and 11.08 g (0.035 moles) of9,10-dihydroxystearic acid were dissolved in 350 ml of tetrahydrofuranin a 1 liter 3-necked round bottom flask equipped with an overheadstirrer, argon inlet and rubber septum. The mixture was heated with aheat-gun to about 35° C. to dissolve the 9,10-dihydroxystearic acid and46.09 g (0.217 moles) of3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]undecane dissolved in 150ml of tetrahydrofurn was transferred to the reaction flask through therubber septum using argon pressure and a steel U-tube. Polymerizationwas initiated by adding 0.1 ml of a solution prepared by dissolving 0.29g of p-toluenesulfonic acid in 10 ml of tetrahydrofuran. Polymer wasisolated by precipitation into a large excess of methanol, filtering andvacuum drying.

EXAMPLE 2

Polymers containing smaller amounts of 9, 10-dihydroxystearic acid wereprepared by following the same procedure as in Example 1, but using thefollowing amounts of monomers.

For polymer containing 4 mole % 9, 10-dihydroxystearic acid 46.09 g(0.217 mole) 3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]-undecane,17.59 g (0.122 moles) 1,4 transcyclohexanedimethanol, 9.22 g (0.078mole) 1,6-henanediol and 5.38 g (0.017 mole) 9,10-dihydroxystearic acid.

EXAMPLE 3

Following the procedure of Example 1, 46.09 g (0.217 mole)3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]undecane was reacted witha mixture of 18.17 g (0.126 mole) 1,4-transcyclohexanedimethanol, 9.81 g(0.083 mole) 1,6-hexanediol and 2.85 g (0.009 mole)9,10-dihydroxystearic acid.

EXAMPLE 4

Following the procedure of Example 1, 46.09 g (0.217 mole) of3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5] undecane was reactedwith a mixture of 24.57 g (0.208 mole) of 1,6-hexanediol and 1.64 g(0.009 mole) of 3,4-dihydroxycinnamic acid.

EXAMPLE 5

Following the procedure of Example 1, 46.09 g (0.217 mole) of3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]undecane was reacted witha mixture of 30.00 (0.208 mole) of trans-cyclohexanedimethanol and 2.36g (0.009 mole) 6,7-dihydroxy-2-naphthalenesulfonic acid.

EXAMPLE 6

Following the procedure of Example 1, 46.09 g (0.217 mole) of3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]undecane was reacted witha mixture of 18.54 g (0.206 mole) of 1,4-butanediol and 1.72 g (0.011mole) of 2,4-dihydroxypyrimidine-5-carboxylic acid.

EXAMPLE 7

Following the procedure of Example 1, 30.81 g (0.217 mole) of1,4-divinyloxybutane was reacted with 21.53 g (0.207 mole)1,5-pentanediol and 3.17 g (0.010 mole) 9, 10-dihydroxystearic acid.

EXAMPLE 8

Following the procedure of Example 1, 34.29 g (0.217 mole) of diethyleneglycol divinyl ether was reacted with 30.58 g (0.212 mole) of1,4-trans-cyclohexanedimethanol and 1.82 g (0.005 mole) of3,6-dihydroxynapthalene-2,7-disulfonic acid.

EXAMPLE 9

Finely ground polymer powders (480 mg), which contained 1 mole of9,10-dihydroxystearic acid, 39.5 mole % of 1,6- hexanediol and 59.5 mole% of 1,4-trans-cyclohexanedimethanol, were mixed with 20 mg ofmonosodium ivermectin-4"-o-phosphate. Powders were compressed intopellet and injection-molded into sheets (0.8 mm in thickness). Discs (8mm diameter) were punched off from the sheet. They were placed in 200 mlof pH 7.4 phosphate buffer solution and agitated vertically at a rate of32 stroke/min at 37° C. The release of drug from the matrix was obtainedover 320 hrs.

What is claimed is:
 1. A controlled release device which comprises:(A) apolymer selected from the group consisting of polyorthoesters,polyacetals, polyketals, polyesters and polyphosphazenes with at leastone labile backbone bond per repeat unit and at least one pendant acidfunctionality per thousand repeat units; and (B) a beneficial substancecapable of being released to an aqueous atmosphere incorporated withinor surrounded by the matrix of said polymer.
 2. The controlled releasedevice of claim 1, wherein the pendant acid functionality is selectedfrom the group consisting of carboxylic, phosphoric, sulfonic andsulfenic.
 3. The controlled release device of claim 1, prepared from adiol containing a pendant acid functionality selected from the groupconsisting of 9,10-dihydroxystearic acid; 3,6-dihydroxynaphthalene2,7-disulfonic acid; 2,4-dihydroxybenzoic acid; 3,4-dihydroxycinnamicacid; 6,7-dihydroxy-2-napthalene sulfenic acid;6,7-dihydroxy-2-naphthalene sulfonic acid; 2,5-dihydroxyphenylaceticacid; 2,4-dihydroxypyrimidine-5-carboxylic acid;4,8-dihydroxyquinoline-2-carboxylic acid; and mixtures thereof; and atleast one additional monomer selected from the group consisting ofesters, acetals and mixtures thereof.